Pentoxifylline (PTX), a methylxanthine drug, produces dose-dependent inhibition of TNF production by human monocytes incubated with endotoxin. Treatment with PTX has also suppressed endotoxin-induced TNF production in normal human volunteers. Furthermore, PTX has improved survival, decreased neutrophil aggregation and adhesion, and decreased organ damage in small animals challenged with endotoxin or live bacteria. Because of these results, PTX has been considered a potential therapy from gram- negative bacterial septic shock in humans. We evaluated the therapeutic efficacy and physiologic events associated with PTX therapy using our large animal model of septic shock. In this model, septic canines develop endotoxemia, bacteremia, and circulating TNF within hours after interaperitoneal implantation of an infected clot. In addition, endotoxemia persists for several days. Distinct from studies in small animals, this model allows survival and serial physiologic and microbiologic determinations over the 28-day time course of septic shock. In our initial evaluation of PTX in septic shock we found that with increasing dose of PTX, survival was ordered (no PTX > low-dose PTX > high-dose PTX). Thus, we found that PTX was harmful in this model of gram-negative bacterial septic shock. PTX produced significant increases in circulating number of total white blood cells and neutrophils. In addition, PTX-treated animals were less febrile than controls. These immunomodulatory effects, which have also been described in other studies of PTX, were of no apparent benefit in the present study. During this past year we undertook an evaluation of a lower-dose PTX regimen, in the hopes that a lower dose might improve survival in sepsis.